Targeted Supramolecular Senolytics by Enzyme-Responsive Disassembly and Intracellular Polymerization

Recent evidence indicates that elimination of senescent cells from tissue can be a therapeutic approach to treat age-related disease, but selective targeting of senescent cells remains a challenge. Here, we report a dual-responsive self-assembly system selectively targeting senescent cells by responding to two hallmark features: elevated reactive oxygen species levels and increased alkaline phosphatase (ALP) activity. The engineered monomer (<i>p</i>-Mito-1), bearing phosphate-protected thiol groups and mitochondrial-targeting moieties, assembles into zwitterionic bioinactive spherical nanostructures with low membrane affinity. In senescent cells, ALP-mediated dephosphorylation of <i>p</i>-Mito-1 triggers disassembly and mitochondrial accumulation of the deprotected monomer (Mito-1), followed by ROS-induced transformation into bioactive fiber structures via disulfide bond formation. This morphological transition exposes surface positive charges, facilitating mitochondrial membrane disruption and the selective activation of apoptosis in senescent cells. In vitro, <i>p</i>-Mito-1 showed selective cytotoxicity toward senescent RPE (SnC_RPE; IC₅₀ ≈ 80 μM) with negligible effects on normal RPE even at 200 μM. We further validated efficacy in an AMD-relevant model, where localized administration selectively depleted senescent RPE cells without overt local toxicity. Our findings demonstrate the potential of dual-responsive supramolecular systems for precise targeting of senescent cells and highlight a modular design strategy for aging-related disease intervention.